Certain 1- (2-naphthyl) and 1- (2- azanaphthyl) -4- (1-phenylmethyl) piperazines; dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     or pharmaceutically acceptable addition salts thereof, wherein:  
     X, Y and Z are the same or different and represent optionally substituted carbon or nitrogen;  
     R 1  and R 2  independently represent organic or inorganic substituents;  
     R 3  and R 4  are variables independently representing inorganic or organic substituents;  
     A represents C 1 -C 4  alkylene; and  
     R 5 , R 6 , and R 7  independently represent hydrogen or C 1 -C 6  alkyl,  
     which compounds bind selectively with high affinity to the dopamine D 4  receptor subtype and are therefore of use in treatment of various neuropsychological disorders.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to certain 1-(2-naphthyl) and1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines and pharmaceuticalcompositions containing such compounds. It also relates to the use ofsuch compounds in the treatment or prevention of psychotic disorderssuch as schizophrenia and other central nervous system diseases.

[0003] 2. Description of the Related Art

[0004] The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has recently beenidentified (Nature, 347: 146 (Sokoloff et al., 1990)). Its uniquelocalization in limbic brain areas and its differential recognition ofvarious antipsychotics suggest that the D₄ receptor may play a majorrole in the etiology of schizophrenia. Selective D₄ antagonists areconsidered effective antipsychotics free from the neurological sideeffects displayed by conventional neuroleptics.

[0005] Various 4-benzylpiperazines have been described. See, forexample, Arch. Med. Res., 25: 435-440 (Terron et al., 1994) and Toxicol.Appl. Pharmacol., 7: 257-267 (Schmidt and Martin, 1965).

SUMMARY OF THE INVENTION

[0006] This invention provides novel compounds which interact withdopamine subtypes. Accordingly, in a broad aspect, the inventionprovides compounds of Formula I:

[0007] or pharmaceutically acceptable addition salts thereof, wherein:

[0008] X, Y and Z are the same or different and represent CR_(c) ornitrogen;

[0009] R_(c) represents hydrogen, halogen or C₁-C₆alkyl;

[0010] R₁ and R₂ independently represent hydrogen, halogen, hydroxy,

[0011] C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂,provided that, when Y and Z represent CH, and R₃ and R₄ are bothhydrogen, R₁ and R₂ are not hydrogen simultaneously; or

[0012] R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or aC₁-C₃ alkylene oxy group;

[0013] R₃ and R₄ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono ordialkyl amino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl;

[0014] A represents C₁-C₄ alkylene; and

[0015] R₅, R₆, and R₇ independently represent hydrogen or C₁-C₆ alkyl.

[0016] Dopamine D₄ receptors are concentrated in the limbic system(Science, 265: 1034 (Taubes, 1994)) which controls cognition andemotion. Therefore, compounds that interact with these receptors areuseful in the treatment of cognitive disorders. Such disorders includecognitive deficits which are a significant component of the negativesymptoms (social withdrawal and unresponsiveness) of schizophrenia.Other disorders include those involving memory impairment or attentiondeficit disorders.

[0017] Compounds of the present invention demonstrate high affinity andselectivity in binding to the D₄ receptor subtype. These compounds aretherefore useful in treatment of a variety of neurospychologicaldisorders, such as, for example, schizophrenia, psychotic depression andmania. Other dopamine-mediated diseases such as Parkinsonism and tardivedyskinesias can also be treated directly or indirectly by modulation ofD₄ receptors.

[0018] Thus, in another aspect, the invention provides methods fortreatment and/or prevention of neuropsychochological or affectivedisorders including, for example, schizophrenia, mania, dementia,depression, anxiety, compulsive behavior, substance abuse, memoryimpairment, cognitive deficits, Parkinson-like motor disorders, e.g.,Parkinsonism and dystonia, and motion disorders related to the use ofneuroleptic agents. In addition, the compounds of the invention areuseful in treatment of depression, memory-impairment impairment orAlzheimer's disease by modulation of D₄ receptors which selectivelyexist in limbic area known to control emotion and cognitive functions.Further, the compounds of the present invention are useful for thetreatment of other disorders that respond to dopaminergic blockade,e.g., substance abuse and obsessive compulsive disorder. These compoundsare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents.

[0019] In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0020] As mentioned above, the invention encompasses substituted1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines ofFormula I. Preferred compounds of Formula I are those where at least oneof R₁ and R₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, orwhere R₁ and R₂ together represent 3,4-methylenedioxy. Still otherpreferred compounds of Formula I are those where

[0021] represents 4-alkylquinolinyl, 4,6-dialkylquinolinyl,4,7-dialkylquinolinyl, 4,8-dialkylquinolinyl, 4-haloquinolinyl, or4-alkyl-6-alkoxyquinolinyl. Preferably, only Z is R_(c). More preferredcompounds of Formula I are those where at least one of R1 and R₂ ischloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula I arethose where R₂ is hydrogen and R₁ is methyl or chloro. In addition,preferred compounds of Formula I are those where A is methylene orethylene, and R₅ is hydrogen.

[0022] Particularly preferred compounds of Formula I are those where

[0023] represents quinolin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl,quinoxalin-2-yl, or naphth-2-yl.

[0024] The invention also encompasses compounds of formula II:

[0025] wherein:

[0026] R₁, R₂, R₃, R₄, R₅, R₆, R_(c), and R₇ carry the same definitionsas set forth above for Formula I.

[0027] Preferred compounds of Formula II are those where at least one ofR₁ and R₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or whereR₁ and R₂ together represent 3,4-methylenedioxy. Still other preferredcompounds of Formula II are those where the both R₃ and R₄ are hydrogen,or the R_(c), R₃ and R₄ substitution on the quinoline ring provides a4-alkylquinolinyl, 4,6-dialkylquinolinyl, 4,7-dialkylquinolinyl,4,8-dialkylquinolinyl, 4-haloquinolinyl, or 4-alkyl-6-alkoxyquinolinylcompound. More preferred compounds of Formula II are those where A ismethylene and at least one of R₁ and R₂ is chloro, fluoro, methyl,ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, orwhere R₁ and R₂ together represent 3,4-methylenedioxy. Particularlypreferred compounds of Formula II are those where R₃ and R₄ arehydrogen, A is methylene, R₂ is hydrogen and R₁ is methyl or chloro.

[0028] Particularly preferred compounds of Formula II are quinolin-2-ylderivatives where R₃ and R₄ are hydrogen. Other particularly preferredcompounds of Formula II are 5,6,7,8-tetrahydroquinolin-2-yl derivativeswhere R₃ and R₄ are hydrogen.

[0029] Also encompassed within the invention are compounds of FormulaIII:

[0030] wherein:

[0031] R₁, R₂, R₃, R₄, R₅, R₆, and R₇ carry the same definitions as setforth above for Formula I.

[0032] Preferred compounds of Formula III are those where at least oneof R₁ and R₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, orwhere R₁ and R₂ together represent 3,4-methylenedioxy. More preferredcompounds of Formula III are those where A is methylene and at least oneof R₁ and R₂ is chloro, fluoro, methyl, ethyl, butyl, isopropyl,n-propyl, trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ togetherrepresent 3,4-methylenedioxy. Particularly preferred compounds ofFormula III are those where R₃ and R₄ are hydrogen, A is methylene, R₂is hydrogen and R₁ is methyl or chloro.

[0033] Particularly preferred compounds of Formula III arequinoxalin-2-yl derivatives where R₃ and R₄ are hydrogen.

[0034] The invention further provides compounds of formula IV:

[0035] wherein:

[0036] R₁, R₂, R₃, R₄, R₅, R₆, and R₇ carry the same definitions as setforth above for Formula I.

[0037] Preferred compounds of Formula IV are those where at least one ofR₁ and R₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or whereR₁ and R₂ together represent 3,4-methylenedioxy. More preferredcompounds of Formula IV are those where A is methylene and at least oneof R₁ and R₂ is chloro, fluoro, methyl, ethyl, butyl, isopropyl,n-propyl, trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ togetherrepresent 3,4-methylenedioxy. Particularly preferred compounds ofFormula IV are those where R₃ and R₄ are hydrogen, A is methylene, R₂ ishydrogen and R₁ is methyl or chloro.

[0038] The invention also encompasses compounds of formula V:

[0039] wherein:

[0040] R₁, R₂, R₃, R₄, R₅, R₆, R_(c), and R₇ carry the same definitionsas set forth above for Formula I.

[0041] Preferred compounds of Formula V are those where R_(c) ishydrogen; and at least one of R₁ and R₂ is halogen, alkyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. More preferred compounds of Formula V are thosewhere R_(c) is hydrogen, A is methylene and at least one of R₁ and R₂ ischloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula V arethose where R₃ and R₄ are hydrogen, A is methylene, R₂ is hydrogen andR₁ is methyl or chloro.

[0042] The particularly preferred compounds of Formula V are naphth-2-ylderivatives where R₃ and R₄ are hydrogen.

[0043] Particularly preferred compounds of Formulae I-V are those whereR₅, R₆, and R₇ are hydrogen.

[0044] The invention further provides intermediates useful in thepreparation of compounds of Formula I. Such intermediates include thoseof Formula VIII.

[0045] where X, Y, Z, R₃, R₄, and R₆ and R₇ are as defined above forFormula I.

[0046] In certain situations, the compounds of this invention I maycontain one or more asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. In these situations, thesingle enantiomers, i.e., optically active forms, can be obtained byasymmetric synthesis or by resolution of the racemates. Resolution ofthe racemates can be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column.

[0047] Representative compounds of the present invention, which areencompassed by Formula I, include, but are not limited to the compoundsin Table I and their pharmaceutically acceptable acid addition salts. Inaddition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

[0048] Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n—ACOOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

[0049] The present invention also encompasses the acylated prodrugs ofthe compounds of Formula I. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

[0050] By the use herein of dashed lines in the structuralrepresentations of the compounds of the invention is meant that thecarbon atoms connected by the dashed line are linked either by single ordouble carbon-carbon bonds.

[0051] The use herein of the following structure

[0052] where A represents C₁-C₄ alkylene and R₅ is hydrogen or loweralkyl (“the AR₅ group”), means alkylene groups having from 1-4 carbonatoms each of which carbon atoms is optionally substituted with a loweralkyl group. Examples of such a structure are methylene, ethylene,propylene, and butylene. A particularly preferred AR₅ group according tothe invention is methylene, i.e., —CH₂—.

[0053] By alkyl or lower alkyl in the present invention is meant C₁-C₆alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbonatoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl.

[0054] By alkoxy or lower alkoxy in the present invention is meant C₁-C₆alkoxy, i.e.,straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0055] By cycloalkoxy in the present invention is meant cycloalkylalkoxygroups having 3-7 carbon atoms where cycloalkyl is defined above.

[0056] By C₁-C₂ alkylene dioxy group is meant a group of the formula:

[0057] where n is 1 or 2.

[0058] By C₁-C₃ alkylene oxy group is meant a group of the formula:

[0059] where n is 1, 2 or 3.

[0060] By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

[0061] Representative compounds of the invention are shown below inTable 1. TABLE 1

[0062] The compounds of the invention are useful in the treatment ofneuropsychological disorders; the pharmaceutical utility of compounds ofthis invention is indicated by the assays for dopamine receptor subtypeaffinity described below in the Examples. The interaction of the1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)-piperazines ofthe invention with dopamine receptor subtypes results in thepharmacological activities of these compounds.

[0063] The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0064] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[0065] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0066] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0067] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0068] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0069] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0070] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0071] The compounds of general formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0072] Compounds of general formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0073] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

[0074] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0075] Representative illustrations of methods suitable for thepreparation of compounds of the present invention are shown in thefollowing Schemes. Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention. For example, incertain situations, protection of reactive moieties such as aminogroups, will be required.

[0076] An azanaphthyl compound of Formula I may be prepared according toScheme 1.

[0077] In Scheme 1, R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, Y, and Z are asdefined above for Formula I.

[0078] As shown, an azanaphthyl compound of general structure VI, havingan appropriate leaving group L at the position indicated, is condensedwith a piperazine compound of general structure VII to provide a1-azanaphthyl piperazine of general structure VIII. Compound VIII maythen be condensed with a benzylic compound of general structure IXhaving an appropriate benzylic leaving group L₂ to provide a1-azanaphthyl-4-(1-phenylmethyl)piperazine of Formula I. The leavinggroups L and L₂ may be halides, sulfonate esters or the like. Thosehaving skill in the art will recognize that the starting materials maybe varied and additional steps employed to produce compounds encompassedby the present invention.

[0079] Alternatively, an azanaphthyl compound of the invention may beprepared according to Scheme 2.

[0080] In Scheme 2, R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, Y and Z are asdefined above for Formula I.

[0081] As shown, an azanaphthyl compound of general structure X, havingan appropriate leaving group L at the position indicated, is condensedwith a 1-substituted piperazine compound of general structure XI toprovide a 1-azanaphthyl-4-(1-phenylmethyl)piperazine of Formula I. Theleaving group L may be a halide, sulfonate ester or the like. Thosehaving skill in the art will recognize that the starting materials maybe varied and additional steps employed to produce compounds encompassedby the present invention.

[0082] Naphthyl compounds of the invention may be prepared according toScheme 3.

[0083] In Scheme 3, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ carry the samedefinitions as set forth above for Formula I.

[0084] As shown, an 2-naphthylpiperazine compound of general structureXII is condensed with a benzylic compound of general structure IX havingan appropriate benzylic leaving group L₂ to provide a1-naphthyl-4-(1-phenylmethyl)piperazine of Formula I. The leaving groupL₂ may be a halide, a sulfonate ester or the like. The startingmaterials are either commercially available or may be prepared usingcommon synthetic methods described within the body of chemicalliterature.

[0085] Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present inventions, as demonstrated by thefollowing examples. In some cases, protection of certain reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general, the need for such protecting groups will beapparent to those skilled in the art of organic synthesis as well as theconditions necessary to attach and remove such groups.

[0086] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0087] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them.

EXAMPLE 1

[0088]

[0089] A solution of 25 g of benzoyleneurea and 12 mL of diethyl anilinein 200 mL of phosphorus oxychloride is refluxed for 4 days after whichexcess phosphorus oxychloride is removed on a rotovap and the remainingresidue poured onto ice. The mixture is then extracted with ethylacetate and the combined organic extracts washed with water, 1 N NaOHsolution, dried and concentrated. The residue is recrystalized fromisopropanol to provide 11 g of the dichloroquinazoline as off-whiteneedles (m.p. 64-66° C.).

[0090] A two-phase mixture of a solution of 2, 4-dichloro-quinazoline (5g) in methylene chloride (100 mL) covered with 100 mL of saturated brinecontaining 9% NH₄OH is treated with powdered zinc (5 g) and theresultant mixture is then refluxed for 4 h, cooled and filtered throughcelite. The organic layer is removed, diluted with ethyl acetate (100ml), washed with 1 N HCl solution, dried and concentrated.

[0091] A solution of 2-chloroquinazoline (5 g) in 20 mL of toluene isadded dropwise to a refluxing solution of piperazine (20 g) in 150 mL oftoluene and the resultant solution refluxed for an additional 24 h.After cooling to 0° C. for 0.5 h, the solution is filtered and thefiltrate extracted with 10% acetic acid. The aqueous extracts are washedwith ether, basified and extracted with toluene. The toluene layer isthen washed with water, dried and concentrated. Finally, the material isplaced under vacuum overnight (6.8 g, m.p. 188-121° C.).

[0092] A solution of 1-quinazolin-2-ylpiperazine (250 mg, 1.2 mmol) and4-chlorobenzyl bromide (220 mg) in acetonitrile (10 mL) containingpotassium carbonate (500 mg) is strirred and heated at 60° C. for 4 h.After cooling the reaction is partitioned between ether and water andthe organic layer extracted with 1 N HCl. The acidic extract is thenbasified, extracted with chloroform and the organic layer is dried andconcentrated to provide the product, which may alternatively be named1-(quinazolin-2-yl)-4-(1-[4-chlorophenyl]methyl) piperazinehydrochloride, as a colorless oil (310 mg, 87%). The oxalate salt isprepared in isopropanol. ¹H NMR (DMSO) 9.2 (s, 1H) , 7.82 (d, J=4 Hz,1H) , 7.72 (T, 1H) ,,7.25-7.5 (m, 6H), 3.9 (m, 4H), 3.75 (s, 2H), 2.75(m, 4H).

EXAMPLE 2

[0093]

[0094] 2-Hydroxyquinoxaline (1.5 g) is heated in phosphorus oxychloride(10 mL) for 12 h.after which the reaction is concentrated and theresidue partitioned between methylene chloride and 1 N NaOH. Theresulting crude chloride is taken up in toluene (10 mL) and thissolution is then added dropwise to a refluxing solution of piperazine (5g) in toluene (40 mL). The resulting solution is refluxed for anadditional 24 h, cooled to 0° C. for 0.5 h, filtered and concentrated.The filtrate is extracted with 10% acetic acid and the aqueous extractswashed with ether, basified and extracted with toluene. The toluenelayer is washed with water, dried and concentrated. The concentratedmaterial, which may alternatively be named quinoxalin-2-ylpiperazine, isplaced under vacuum overnight (1.2 g, 77%, m.p. 74-76 ° C.). ¹H NMR(CDCl₃) 8.6 (s, 1H) , 7.87 (dd, J=8, 1 Hz, 1H), 7.68 (dd, J=8, 1 Hz,1H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 3.76(t, J=5 Hz, 4H), 3.02 (t, J=5 Hz, 4H).

[0095] A solution of quinoxalin-2-ylpiperazine (325 mg, 1.53 mmol) and4-methylbenzyl bromide (340 mg) in acetonitrile (10 mL) containingpotassium carbonate (500 mg) is strirred and heated at 60° C. for 4 h.After cooling, the reaction is partitioned between ether and water andthe organic layer extracted with 1 N HCl. The acidic extract is thenbasified and extracted with chloroform. The organic layer is dried andconcentrated to provide the product as a colorless oil (320 mg, 66%).The oxalate salt is prepared in isopropanol.

EXAMPLE 3

[0096] The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2:

[0097] (a) 1-(quinazolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazineoxalate (m.p. 207-209° C.)

[0098] (b) 1-(quinoxalin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazineoxalate (m.p. 209-212° C.)

[0099] (c)1-(3-methylquinoxalin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide (m.p. 293-295° C.)

[0100] (d) 1-(quinolin-2-yl)-4-(1-[4-methylphenyl]methyl)piperazinehydrochloride (m.p. 278-280° C.)

[0101] (e) 1-(quinolin-2-yl)-4-(1-[4-ethylphenyl]methyl)piperazine

[0102] (f) 1-(quinolin-2-yl)-4-(1-[4-isopropylphenyl]methyl)piperazinehydrochloride (m.p. 270-271° C.)

[0103] (g) 1-(quinolin-2-yl)-4-(1-[4-tert-butylphenyl]methyl)piperazinehydrochloride (m.p. 285-287° C.)

[0104] (h) 1-(quinolin-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine

[0105] (i) 1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide (m.p. 268-271° C.)

[0106] (j) 1-(quinolin-2-yl)-4-(1-[3,4-dichlorophenyl]-methyl)piperazinehydrobromide (m.p. 285-287° C.)

[0107] (k)1-(quinolin-2-yl)-4-(1-[4-trifluoromethylphenyl]methyl)piperazinehydrobromide (m.p. 271-273° C.)

[0108] (l)1-(quinolin-2-yl)-4-(1-[4-trifluoromethoxyphenyl]methyl)piperazine (m.p.109-110° C.)

[0109] (m)1-(quinolin-2-yl)-4-(1-[3,4-methylenedioxyphenyl]methyl)piperazinehydrobromide (m.p. 279-280° C.)

[0110] (n)1-(4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide (m.p. 215-217° C.)

[0111] (o)1-(4,6-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide

[0112] (p)1-(4,7-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide (m.p. 295-296° C.)

[0113] (q)1-(4,8-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide (m.p. 262-264° C.)

[0114] (r) 1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]ethyl)piperazinehydrobromide (m.p. 285-287° C.)

[0115] (s) 1-(4-fluoroquinolin-2-yl)-4-(phenylmethyl)piperazine oxalate(m.p. 186-187° C.)

[0116] (t)1-(4-fluoroquinolin-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine oxalate(m.p. 191-193° C.)

EXAMPLE 4

[0117]

[0118] Dihydroxyquinazoline (10 g) is dissolved in phosphorusoxychloride (100 mL) and diethyl aniline (15 g). The resulting darksolutuion is brought to reflux for 24 h, cooled and concentrated. Theresidue is taken up in chloroform, washed with ice cold 1N NaOHsolution, dried and concentrated. The resulting solid is recrystallizedfrom ethyl acetate to provide the dichloro compound (9.2 g, 76%.

[0119] 2, 4-Dichloro-5,6,7,8-tetrahydroquinazoline (4 g) is dissolved in50 mL of methylene chloride and the resulting solution covered with 9%NH₄OH in saturated brine. Zinc (4 g) is added and the resulting mixturegently refluxed overnight. After filtration through celite, the organiclayer is washed with water, dried and concentrated.

[0120] A solution of 1 g of 2-hydroxy-5,6,7,8-tetrahydroquinazoline and0.1 g of diethylaniline in 10 mL of phosphorus oxychloride is refluxedfor 2 h, and subsequently cooled and concentrated. The residue is takenup in chloroform and washed with excess 3 N NaOH solution. The organiclayer is dried and concentrated to provide2-chloro-5,6,7,8-tetrahydroquinazoline (1.1 g) as an orange solid.

[0121] A portion of this material (200 mg, 1.2 mmol) is mixed neat withan equivalent amount of 1-(4-chlorobenzyl)piperazine (250 mg) and theresultant mixture is heated to 150° C. under nitrogen for 30 min. Uponcooling, the resulting homogenous mixture is partitoned betweenchloroform and 10% NH₄OH solution. The organic layer is dried andconcentrated. The residue is then taken up in hot isopropanol (3 mL) andtreated with oxalic acid (108 mg) in a minimum amount of hot isopropanolto provide the desired product, which may also be named as2-((4-(4-chlorophenyl)-piperazinyl)methyl)-5,6,7,8-tetrahydroquinazoline,oxalic acid salt, as an off-white solid (213 mg, 41%, m.p. 210-212° C.).

EXAMPLE 4

[0122]

[0123] A solution of 0.7 g of 2-hydroxy-5,6,7,8,-tetrahydroquinoline(prepared according to the methods outlined by Meyers et al., J. Org.Chem., 29: 1435-1438, 1964) and 0.1 g of diethylaniline in 7 mL ofphosphorus oxychloride is refluxed for 2h, cooled and concentrated. Theresidue taken is up in chloroform, washed with excess 3 N NaOH solutionand the organic layer dried and concentrated to provide crude2-chloro-5,6,7,8-tetrahydro-quinoline (0.45 g) as an oil.

[0124] A portion of this material (150 mg, 0.9 mmol) is mixed neat withan equivalent amount of 1-(4-chlorobenzyl)piperazine (189 mg) and theresultant mixture heated to 150° C. under nitrogen for 20 min. Uponcooling, the resulting homogenous mixture is triturated with isopropanolto provide the desired product, which may alternatively be named as4-(4-chlorophenyl)-1-(2-5,6,7,8-tetrahydroquinolylmethyl)piperazine,hydrobromide salt, as an off-white solid (274 mg, 81%, m.p. 281-283° C.). ¹H NMR (CDCl₃) 7.31 (s, 4H), 7.18 (d, J=4 Hz, 1H), 6.42 (d, J=4 Hz,1H), 3.56 (s, 2H), 3.52 (m, 4H), 2.75 (m, 2H), 2.6 (m, 6H), 1.7-1.85 (m,4H).

[0125] The following compound is prepared essentially according to theprocedures set forth above in Examples 3 and 4:

[0126] (a)1-(6-methoxy-4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrochloride (m.p. 250-253° C.)

EXAMPLE 5

[0127]

[0128] A mixture of phosphorus pentoxide (17 g) and triethyl aminehydrochloride (16.5 g) is heated and stirred under nitrogen until melted(240° C.). To this mixture is then added 2-aminonaphthalene (5.72 g) anddiethanolamine (4.2 g), and the temperature maintained for 0.5 h. Aftercooling to approx. 100° C., the mixture is poured onto ice, neutralizedwith 1N NaOH, and extracted with chloroform. The organic layer is washedwith water, dried and concentrated. The hydrochloride salt is preparedin ethanol (8.1 g, m.p. 265-266° C.)

[0129] A solution of 1-(naphth-2-yl)piperazine (212 mg, 1 mmol) and4-methylbenzyl bromide (185 mg, 1 mmol) in acetonitrile (10 mL) overpotassium carbonate (500 mg) is stirred for 48 h. After partitioningbetween ether and water, the organic layer is extracted with 1N HClsolution, and the acidic layer is then neutralized with 6 N sodiumhydroxide and extracted with chloroform. The combined chloroformextracts are dried over sodium sulfate and concentrated. The resultingoil is taken up in isopropanol and treated with a saturated solution ofHCl (g) in ethyl acetate to provide the product as a white crystallinesolid (374 mg, 86%).

EXAMPLE 6

[0130] The following compounds are prepared essentially according to theprocedures set forth above in Example 5:

[0131] (a) 1-(naphth-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrochloride (m.p. 216-218° C.)

[0132] (b) 1-(naphth-2-yl)-4-(1-[4-methylphenyl]methyl)piperazinehydrobromide (m.p. 222-223° C.)

[0133] (c) 1-(naphth-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazinehydrobromide (m.p. 244-246° C.)

[0134] (d) 1-(naphth-2-yl)-4-(1-[3-fluorophenyl]methyl)piperazinehydrobromide (m.p. 253-255° C.)

[0135] (e) 1-(naphth-2-yl)-4-(1-[2-fluorophenyl]methyl)piperazinehydrobromide (m.p. 239-240° C.)

EXAMPLE 7

[0136] Assay for D₂ and D₄ Receptor Binding Activity

[0137] The pharmaceutical utility of compounds of this invention isindicated by the assays for dopamine receptor subtype affinity describedbelow.

[0138] Pellets of COS cells containing recombinantly produced D₂ or D₄receptors from African Green monkey are used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 40°C. and pH 7.4. The sample is then centrifuged at 30,000×g andresuspended and rehomogenized. The sample is again centrifuged asdescribed above and the final tissue sample is frozen until use. Thetissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing100 mM NaCl.

[0139] Incubations are carried out at 48° C. and contain 0.4 ml oftissue sample, 0.5 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding is defined as that binding found in the presence of1 mM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding. Binding characteristics for examples ofcompounds encompassed within Formula I for the D₂ and D₄ receptorsubtypes are shown in Table 2 for rat striatal homogenates. TABLE 2Binding of compounds of the invention to D₄ and D₂ receptors cloned fromAfrican Green monkey. Compound Number D₄ K_(i) (nM) D₂ K_(i) (nM) 28 >4000 3 11 >4000 6 9 >4000 7 7 1927

[0140] Compound numbers in Table 2 relate to compounds shown in Table 1.

[0141] The binding characteristics of compounds of Formula I for the D₄receptor, expressed in nM, generally range from about 0.5 nanomolar (nM)to about 25 nanomolar (nM). These compounds typically have bindingconstants for the D₂ receptor of from about 200 nM to more than 1000 nM.Thus, the compounds of the invention are generally at least about 10time more selective for the D₄ receptor than the D₂ receptor.Preferably, these compounds are at least 20, and more preferably atleast 25-50, times more selective for the D₄ receptor than the D₂receptor. Most preferably, these compounds are at least 100 times moreselective for the D₄ receptor than the D₂ receptor.

EXAMPLE 8

[0142] A compound described in Arch. Med. Res., 25: 435-440 (Terron etal., 1994), 1-(quinolin-2-yl)-4-benzylpiperazine (Comparative CompoundB), was evaluated in the assays described above. Comparative Compound Bdemonstrated relatively weak interaction with the D₄ receptor subtype(IC₅₀ =194 nM).

[0143] A compound described in Toxicol. Appl. Pharmacol., 7: 257-267(Schmidt and Martin, 1965), 1-naphth-2-yl-4-benzylpiperazine(Comparative Compound A), was evaluated in the assays described above.Comparative Compound A demonstrated relatively weak interaction with theD₄ receptor subtype (IC₅₀ =33 nM).

[0144] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compounds of the formula:

or pharmaceutically acceptable addition salts thereof, wherein: X, Y andZ are the same or different and represent CR_(c) or nitrogen; R_(c)represents hydrogen, halogen or C₁-C₆alkyl; R₁ and R₂ independentlyrepresent hydrogen, halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl,trifluoromethoxy or SO₂NH₂, provided that, when Y and Z represent CH,and R₃ and R₄ are both hydrogen, R₁ and R₂ are not hydrogensimultaneously; or R₁ and R₂ together represent a C₁-C₂ alkylene dioxygroup or a C₁-C₃ alkylene oxy group; R₃ and R₄ are the same or differentand represent hydrogen, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio,hydroxy, amino, mono or dialkyl amino where each alkyl is C₁-C₆ alkyl,cyano or trifluoromethyl; A represents C₁-C₄ alkylene; and R₅, R₆, andR₇ independently represent hydrogen or C₁-C₆ alkyl.
 2. A compoundaccording to claim 1, wherein at least one of R₁ and R₂ is halogen,alkyl, trifluoromethyl, trifluoromethoxy, or R₁ and R₂ togetherrepresent 3,4-methylenedioxy.
 3. A compound according to claim 1,wherein at least one of R₁ and R₂ is chloro, fluoro, methyl, ethyl,butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, or R₁ andR₂ together represent 3,4-methylenedioxy.
 4. A compound according toclaim 1, wherein R₃ and R₄ are hydrogen, A is methylene, R₂ is hydrogenand R₁ is methyl or chloro.
 5. A compound of the formula:

or the pharmaceutically acceptable addition salts thereof, wherein:R_(c) is hyrogen, halogen, or C₁-C₆ alkyl; R₁ and R₂ independentlyrepresent hydrogen, halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl,trifluoromethoxy or SO₂NH₂, provided that, when R_(c), R₃ and R₄ are allhydrogen, R₁, and R₂ are not hydrogen simultaneously; or R₁ and R₂together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxygroup; R₃ and R₄ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono ordialkyl amino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl;A represents C₁-C₄ alkylene; and R₅, R₆, and R₇ are the same ordifferent and represent hydrogen or C₁-C₆ alkyl.
 6. A compound accordingto claim 5, wherein

represents 4-alkylquinolinyl, 4,6-dialkylquinolinyl,4,7-dialkylquinolinyl, 4,8-dialkylquinolinyl, 4-haloquinolinyl, or4-alkyl-6-alkoxyquinolinyl.
 7. A compound of the formula:

or pharmaceutically acceptable addition salts thereof, wherein: R₁ andR₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy or SO₂NH₂; or R₁ and R₂ togetherrepresent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group; R₃and R₄ are the same or different and represent hydrogen, halogen, C₁-C₆alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl aminowhere each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; A representsC₁-C₄ alkylene; and R₅, R₆, and R₇ independently represent hydrogen orC₁-C₆ alkyl.
 8. A compound of the formula:

or pharmaceutically acceptable addition salts thereof, wherein: R₁ andR₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy or SO₂NH₂; or R₁ and R₂ togetherrepresent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group; R₃and R₄ are the same or different and represent hydrogen, halogen, C₁-C₆alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl aminowhere each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; R₅, R₆, andR₇ are the same or different and represent hydrogen or C₁-C₆ alkyl.
 9. Acompound of the formula:

or pharmaceutically acceptable addition salts thereof, wherein: R_(c) ishydrogen, halogen or C₁-C₆ alkyl; R₁ and R₂ independently representhydrogen, halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl,trifluoromethoxy or SO₂NH₂; or R₁ and R₂ together represent a C₁-C₂alkylene dioxy group or a C₁-C₃ alkylene oxy group; R₃ and R₄independently represent hydrogen, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,alkylthio, hydroxy, amino, mono or dialkyl amino, cyano ortrifluoromethyl; R₅, R₆, and R₇ independently represent hydrogen orC₁-C₆ alkyl.
 10. A compound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-methylphenyl]methyl)piperazine.
 11. A compoundaccording to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-ethylphenyl]methyl)piperazine.
 12. A compoundaccording to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-tert-butylphenyl]methyl)piperazine.
 13. Acompound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine.
 14. A compoundaccording to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.
 15. A compoundaccording to claim 1, which is1-(quinolin-2-yl)-4-(1-[3,4-dichlorophenyl]methyl)piperazine.
 16. Acompound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-trifluoromethylphenyl]methyl)piperazine.
 17. Acompound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-trifluoromethoxyphenyl]methyl)piperazine. 18.A compound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[3,4-methylenedioxyphenyl]methyl)piperazine. 19.A compound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-sulfonamidophenyl]methyl)piperazine.
 20. Acompound according to claim 1, which is1-(5,6,7,8-tetrahydroquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.21. A compound according to claim 1, which is1-(4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.
 22. Acompound according to claim 1, which is1-(4,6-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.23. A compound according to claim 1, which is1-(4,7-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.24. A compound according to claim 1, which is1-(4,8-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.25. A compound according to claim 1, which is1-(6-methoxy-4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.26. A compound according to claim 1, which is1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]ethyl)piperazine.
 27. A compoundaccording to claim 1, which is1-(4-fluoroquinolin-2-yl)-4-(1-phenylmethyl)piperazine.
 28. A compoundaccording to claim 1, which is1-(4-fluoroquinolin-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine.
 29. Acompound according to claim 1, which is1-(quinoxalin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.
 30. Acompound according to claim 1, which is1-(3-methylquinoxalin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine. 31.A compound according to claim 1, which is1-(quinazolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.
 32. Acompound according to claim 1, which is1-(5,6,7,8-tetrahydroquinazolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.33. A compound according to claim 1, which is1-(naphth-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine.
 34. A compoundaccording to claim 1, which is1-(naphth-2-yl)-4-(1-[4-methylphenyl]methyl)piperazine.
 35. A compoundaccording to claim 1, which is1-(naphth-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine.
 36. A compoundaccording to claim 1, which is1-(naphth-2-yl)-4-(1-[3-fluorophenyl]methyl)piperazine.
 37. A compoundaccording to claim 1, which is1-(naphth-2-yl)-4-(1-[2-fluorophenyl]methyl)piperazine.
 38. A compoundof the formula

where X, Y and Z are the same or different and represent CR_(c) ornitrogen; R_(c) represents hydrogen, halogen or C₁-C₆ alkyl; R₃ and R₄are the same or different and represent hydrogen, halogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino whereeach alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; A representsC_(l)-C₄ alkylene; and R₆ and R₇ independently represent hydrogen orC₁-C₆ alkyl.
 39. A compound according to claim 38, wherein X and Y arenitrogen and Z is CH.
 40. A compound according to claim 38, wherein X,Y, and Z are CH.
 41. A compound according to claim 38, wherein X and Zare nitrogen and Y is CH.